Tumor metastasis to the vital organs is a major cause of mortality in cancer patients. In fact, tumor metastasis is the cause for more than 90% of cancer mortalities. Although our understanding of tumor cell biology has increased exponentially during the last decade, we still know very little about the role tumor microenvironment plays in promoting tumor cell release from the primary tumor and metastasis to the distal organs. Angiogenesis plays an important role in tumor metastasis by providing an increased density of immature, highly permeable blood vessels. It is estimated that from a 1 cm primary tumor as many as 2 million tumor cells can be shed each day into the circulation, though very few of these tumor cells ever form metastases. Most of the cancer cells, particularly epithelial origin cancer cells, have very low survival rates in circulation and undergo rapid cell death. In addition to circulating tumor cells, increased levels of circulating endothelial cells are also observed in cancer patients with progressive disease. Interestingly, in our preliminary studies we have observed a marked increase in Bcl-2 positive circulating endothelial cells in the blood samples of head and neck cancer patients. Similarly, Mancuso and co-workers have recently shown that increased levels of activated endothelial cells are released in circulation of cancer patients. Our preliminary results suggest that these activated endothelial cells may be coming from primary tumors. These exciting results raise an intriguing question about the biological significance of these activated circulating endothelial cells. Based on our previous studies and preliminary findings, we hypothesize that endothelial cells expressing Bcl-2 bind to tumor cells, protect them in circulation from anoikis and chaperone these tumor cells to the distal sites. The specific aims are thus designed to test this hypothesis in a systematic and detailed manner. This hypothesis will be tested by investigating if Bcl-2 expression in endothelial cells enhances adhesion molecule expression and tumor cell binding in aim 1. In aim 2, we will examine if endothelial cells expressing Bcl-2 protect tumor cells against anoikis and chaperone these tumor cells to distal sites. This study may provide a new insight into how tumor stroma contributes to tumor metastasis and help us identify new potential targets to block tumor metastasis to vital organs.